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【结 构 式】 
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【分子编号】42654 【品名】methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate 【CA登记号】 |
【 分 子 式 】C13H18O4 【 分 子 量 】238.28352 【元素组成】C 65.53% H 7.61% O 26.86% |
合成路线1
该中间体在本合成路线中的序号：(II)The intermediate (XV) has been obtained as follows: The reaction of methyl 3-hydroxy-2(S)-methylpropionate (I) with 4-methoxybenzyl trichloroacetimidate gives methyl 3-(4-methoxybenzyloxy)-2(S)-methylpropionate (II), which is reduced with LiAlH4, yielding the primary alcohol (III). The Swern oxidation of (III) affords the aldehyde (IV), which is condensed with the chiral imidazolidinone (V) to provide the adduct (VI). The transamidation of (VI) with N,O-dimethylhydroxylamine by means of Me3Al gives the methoxyamide (VII), which is debenzylated with DDQ to yield the diol (VIII). The reaction of (VIII) with 4-methoxybenzaldehyde diethylacetal (IX) and CSA affords the cyclic ketal (X), which is condensed with the propionyloxazolidinone (XI) by means of dibutylboron triflate to furnish the adduct (XII). The silylation of the OH group of (XII) with Tbdms-OTf gives the silyl ether (XIII), which is reduced at the amide group with LiBH4 to yield the primary alcohol (XIV). Finally, this compound is treated with I2 and PPH3 to afford the intermediate iodo derivative (XV).
| 【1】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823. |
| 【2】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (III) | 42655 | (2R)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-propanol | C12H18O3 | 详情 | 详情 | |
| (IV) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (V) | 42657 | (4R,5S)-3-[(Z)-1-butoxy-1-propenyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C17H23NO3 | 详情 | 详情 | |
| (VI) | 42658 | (4R,5S)-3-[(2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C25H31NO6 | 详情 | 详情 | |
| (VII) | 42659 | (2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide | C17H27NO5 | 详情 | 详情 | |
| (VIII) | 42660 | (2R,3S,4S)-3,5-dihydroxy-N-methoxy-N,2,4-trimethylpentanamide | C9H19NO4 | 详情 | 详情 | |
| (IX) | 35670 | 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether | C12H18O3 | 详情 | 详情 | |
| (X) | 42661 | (2R)-N-methoxy-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-N-methylpropanamide | C17H25NO5 | 详情 | 详情 | |
| (XI) | 10968 | (4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone | 184363-65-3 | C12H13NO3 | 详情 | 详情 |
| (XII) | 42662 | (4R)-4-benzyl-3-[(2R,3S,4S)-3-hydroxy-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C28H35NO7 | 详情 | 详情 | |
| (XIII) | 42663 | (4R)-4-benzyl-3-[(2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C34H49NO7Si | 详情 | 详情 | |
| (XIV) | 42664 | (2S,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-1-pentanol | C24H42O5Si | 详情 | 详情 | |
| (XV) | 42665 | tert-butyl(dimethyl)silyl (1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl ether; tert-butyl[((1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl)oxy]dimethylsilane | C24H41IO4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVI)Synthesis of the target (+)-Discodermolide: The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with p-methoxybenzyl trichloroacetimidate gives the benzyl ether (XXVI), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (XXVII). The reaction of (XXVII) with 2-methylpropenal (XXVIII) by means of (c-Hex)2B-Cl and TEA in ethyl ether affords the chiral hydroxyketone (XXIX), which is reduced with SmI2 and propanal to provide the beta-diol monoester (XXX). The methanolysis of (XXX) by means of K2CO3 furnishes the diol (XXXI), which can also be obtained directly by reduction of (XXIX) with Me4NBH(OAc)3 in acetonitrile/AcOH. The reaction of (XXXI) with the diethylacetal (XXXII) and PPTS in refluxing toluene gives the phenylselenoacetal (XXXIII), which is oxidized with NaIO4 and treated with DBU to achieve a Claisen rearrangement and yield the eight member lactone (XXXIV). The hydrolysis of (XXXIV) with KOH in refluxing aqueous methanol affords the hydroxyacid (XXXV), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP in dichloromethane to provide the phenyl ester (XXXVII). The reaction of (XXXVII) with Tbdms-OTf and lutidine gives the silylated ester (XXXVIII). Alternatively, the methanolysis of the lactone (XXXIV) with NaOMe in methanol gives the hydroxyester (XXXIX), which is treated with Tbdms-OTf as before to yield the silylated ester (XL). The hydrolysis of the ester (XL) with KOH in refluxing aqueous methanol affords the silylated hydroxyacid (XLI), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP to provide the already reported phenyl ester (XXXVIII).
| 【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (XXVI) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (XXVII) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (XXVIII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (XXIX) | 42615 | (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one | C18H26O4 | 详情 | 详情 | |
| (XXX) | 62842 | (1R)-1-{(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl}-2-methyl-2-propenyl butyrate | C22H34O5 | 详情 | 详情 | |
| (XXXI) | 62843 | (3R,4R,5S,6S)-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-1-heptene-3,5-diol | C18H28O4 | 详情 | 详情 | |
| (XXXII) | 62844 | 1-[(2,2-dipropoxyethyl)selanyl]benzene; 2-(phenylselanyl)-1-propoxyethyl propyl ether | C14H22O2Se | 详情 | 详情 | |
| (XXXIII) | 42618 | (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether | C26H34O4Se | 详情 | 详情 | |
| (XXXIV) | 42620 | (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one | C20H28O4 | 详情 | 详情 | |
| (XXXV) | 62845 | (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid | C20H30O5 | 详情 | 详情 | |
| (XXXVI) | 37388 | 2,6-dimethylphenol | 576-26-1 | C8H10O | 详情 | 详情 |
| (XXXVII) | 62847 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C28H38O5 | 详情 | 详情 | |
| (XXXVIII) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 | |
| (XXXIX) | 62846 | methyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C21H32O5 | 详情 | 详情 | |
| (XL) | 42621 | methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C27H46O5Si | 详情 | 详情 | |
| (XLI) | 62848 | (Z,6S,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid | C26H44O5Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Synthesis of the chiral 5-oxopentanoic ester intermediate (XI): The reaction of 3-hydroxy-2(S)-methylpentanoic acid methyl ester (I) with 4-methoxybenzyl trichloroacetimidate gives the aryl ether (II), which is treated with ethylmagnesium bromide to yield the ketone (III). The condensation of (III) with formaldehyde by means of (c-Hex)2B-Cl and H2O2 affords the hydroxypentanone (IV), which is reduced by means of NaBH(OAc)3 in THF/AcOH to provide the diol (V). The regioselective oxidation of the primary alcohol of (V) with TEMPO and BAIB in dichloromethane gives the beta-hydroxyaldehyde (VI), which is further oxidized with NaClO2 yielding the carboxylic acid (VII). The esterification of (VII) by means of Me-I and K2CO3, or with TMS-CHN2 affords the methyl ester (VIII), which is treated with Tbdms-OTf and lutidine to provide the silyl ether (IX). The selective deprotection of (IX) by means of DDQ in dichloromethane furnishes the omega-hydroxyester (X), which is finally submitted to a Swern oxidation to yield the chiral 5-oxopentanoic ester intermediate (XI).
| 【1】 Paterson, I.; Delgado, O.; Florence, G.J.; Lyothier, I.; Scott, J.P.; Sereinig, N.; 1,6-asymmetric induction in boron-mediated aldol reactions: Application to a practical total synthesis of (+)-discodermolide. Org Lett 2003, 5, 1, 35. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (III) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (IV) | 62852 | (2S,4S)-1-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethyl-3-pentanone | C15H22O4 | 详情 | 详情 | |
| (V) | 62853 | (2S,3R,4S)-5-[(4-methoxybenzyl)oxy]-2,4-dimethyl-1,3-pentanediol | C15H24O4 | 详情 | 详情 | |
| (VI) | 62854 | (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal | C15H22O4 | 详情 | 详情 | |
| (VII) | 62855 | (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoic acid | C15H22O5 | 详情 | 详情 | |
| (VIII) | 62856 | methyl (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoate | C16H24O5 | 详情 | 详情 | |
| (IX) | 62857 | methyl (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoate | C22H38O5Si | 详情 | 详情 | |
| (X) | 62858 | methyl (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-2,4-dimethylpentanoate | C14H30O4Si | 详情 | 详情 | |
| (XI) | 62859 | methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-oxopentanoate | C14H28O4Si | 详情 | 详情 |